权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigating the strain-specific role of Bacteroides in the etiology of Alzheimer's disease

研究拟杆菌在阿尔茨海默病病因学中的菌株特异性作用

基本信息

批准号：
10381224
负责人：
Laura Michelle Cox
金额：
$ 43.49万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10381224
关键词：
APP-PS1 Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Animal Model Bacteria Bacteroides Bacteroides fragilis Brain Cell Wall Chronic Comparative Genomic Analysis DNA Sequence Alteration Data Degradation Pathway Diagnosis Disease Endoplasmic Reticulum Etiology Exhibits Gene Expression Genes Genetic Transcription Genomics Histologic Human Impairment In Vitro Infectious Agent Insulinase Intestines Lead Measures Memory Metagenomics Metronidazole Microglia Molecular Mus Nature Neurons Neurotransmitters Pathogenesis Pathway interactions Phagocytosis Play Prevention Process Proteins Research Role Senile Plaques Shotguns Signal Pathway Testing Tight Junctions Toxin Variant Virulence Factors acute infection aged base fragilysin gut microbiota human disease immunoreactivity immunoregulation in vitro Assay in vivo inflammatory disease of the intestine insight macrophage microbiota monocyte mouse model nervous system disorder neuron loss neurotoxicity nonalzheimer dementia novel prevent protein degradation response stool sample systemic inflammatory response tau Proteins tau aggregation tau phosphorylation tau-1 transcriptomics

项目摘要

PROJECT SUMMARY While an infectious etiology has been proposed to be involved in the initiation and progression of Alzheimer’s disease (AD), more evidence is needed to support the roles of specific infectious agents and to identify mechanisms by which they act. Given the chronic nature of AD and based on our discoveries in animal models of AD, we hypothesize that a chronic and sub-acute infection with specific Bacteroides strains contributes to AD by affecting Ab and tau phosphorylation, aggregation, and clearance, and contributing to neuronal toxicity. In support of our hypothesis, we were the first group to demonstrate that Bacteroides not only correlated with Ab levels in the brain, but actually increased amyloid plaques when administered to animal models of AD. Strikingly, Bacteroides is elevated in AD, correlates with CSF levels of Ab42 and phospho-tau, and is associated with markers of gut inflammation in AD patients, suggesting a direct relevance to human disease. In our preliminary data, we found that B. fragilis affected cortical expression of genes involved in APP and tau phosphorylation that promote their aggregation, as well as genes related to memory and neuronal death. We also found that Bacteroides downregulated microglial genes important for the clearance of Ab. Depletion of Bacteroides with metronidazole decreased amyloid plaques, increased cortical expression of insulin degrading enzyme, which can degrade Ab, and affected genes involved in multiple protein degradation pathways. We found that Bacteroides could impair macrophage Ab phagocytosis in vitro and in vivo. Importantly, we found that transfer of human gut microbiota from AD patients into mice affected similar microglia genes involved in protein degradation and clearance, as well as pathways related to neuronal cell death, suggesting that the AD gut microbiota may harbor infectious agents that contribute to the disease process. Because Bacteroides species are highly prevalent in humans and exhibit a high degree of functional variation among strains, it is not likely that all Bacteroides contribute to AD. In this proposal, we will modify Koch’s postulates to detect Bacteroides strains associated with AD vs. healthy controls and non-AD dementia controls, isolate these strains in pure culture, and use in vitro assays to optimize strain selection for in vivo studies. We will then transfer AD-derived strains to WT mice and animal models of AD, measure AD pathology, and re-isolate our AD-derived strains to determine whether they play a causal role. To investigate potential mechanisms, we will also investigate whether AD strains can affect APP and tau aggregation and clearance, neuronal toxicity, or disrupt transcriptional networks in microglia and neurons. By investigating the molecular and functional diversity in Bacteroides in AD, our studies have the potential to identify novel pathogenicity factors in Bacteroides that could be used both for the diagnosis and treatment of AD.

项目总结